Sirolimus (offered commercially by Wyeth as RAPAMUNE) is a macrocyclic lactone produced by Streptomyces hygroscopicus used for immunosuppression following renal transplantation. The chemical name of sirolimus (also known as rapamycin) is (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13, -14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethox-y-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacycloh-entriacontine-1,5,11,28,29(4H,6H,31H)-pentone. The molecular formula thereof is C51H79NO13 and the molecular weight is 914.2. The structural formula of sirolimus is shown below:

The commercially available product containing sirolimus is RAPAMUNE. Sirolimus inhibits T lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation; it also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle. In rodent models of autoimmune disease, sirolimus suppresses immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis.
Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile. Sirolimus is characterized in that it has a very low solubility in water (only 2.6 μg/ml); therefore only about 0.65 mg of sirolimus is dissolved in a volume of 250 ml of gastrointestinal fluid which is not enough to cause therapeutic effect. To ensure that all sirolimus from the oral dosage form is dissolved in the gastrointestinal fluid, sirolimus is available as an oral solution containing 1 mg/ml of sirolimus and as tablet containing 1 mg or 2 mg of nanosized (less than 400 nm) particles of sirolimus. However preparation of an oral solution of sirolimus before administration requires a special procedure and is thus less preferable from the patient's point of view. Sirolimus in the form of a solid dispersion is described in WO 97/03654. Preparation of tablets containing nanosized particles of sirolimus is described in U.S. Pat. No. 5,989,591. The preparation of nanosized particles of sirolimus and the preparation of sirolimus tablets containing nanosized particles of sirolimus are both complex procedures and may result in batch-to-batch variations in the dissolution of sirolimus from the tablets. Therefore an alternative approach for the enhancement of sirolimus solubility is desirable. Sirolimus is available in the form of crystalline powder. It is known to a skilled person that the transformation of the crystalline form of a low solubility drug to the amorphous form can significantly increase the solubility thereof, which is also true for sirolimus. However amorphous sirolimus is extremely chemically unstable and is therefore not easily acceptable for the incorporation into an oral pharmaceutical dosage form. Pharmaceutical dosage forms comprising amorphous sirolimus are described in WO 06/039237 and WO 06/094507. In WO 06/094507, a modified release pharmaceutical formulation comprising sirolimus and glyceryl monostearate at a concentration of 49.25% is described. The release rate of sirolimus from the delayed release rate formulations disclosed in WO 06/094507 is significantly suppressed compared to the marketed sirolimus formulation (RAPAMUNE).
The present invention is aimed at mitigating the problems described above. It relates to a stable pharmaceutical formulation in a solid dosage form for oral administration with enhanced dissolution properties of sirolimus.